Review Question - QID 214974

This patient’s presentation with watery diarrhea, painful oral ulcerations, and macrocytic anemia (low hemoglobin and elevated MCV) in the setting of recent initiation of methotrexate is suggestive of drug-induced side effects. The treatment for these side effects of methotrexate is folate supplementation.

Methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which functions to reduce dihydrofolate to its active intracellular metabolite, tetrahydrofolate. Tetrahydrofolate is a single-carbon carrier that is used by the enzyme thymidylate synthase in nucleotide synthesis. Since methotrexate interferes with this pathway, it induces a state of functional folate depletion, which is thought to result in its gastrointestinal (GI), hematologic, and mucosal side effects. Rapidly dividing cells, such as those found in the GI tract, bone marrow, and mucosal surfaces, have the highest folate demand due to their high metabolic activity and thus are the most susceptible to methotrexate. Other side effects of methotrexate include mucositis, mild transaminitis, thyroid abnormalities, hypersensitivity pneumonitis, and pulmonary fibrosis. Folate deficiency causes a megaloblastic anemia, which manifests with a high MCV. Folate supplementation can prevent these side effects in patients who are on chronic, low-dose methotrexate.

Incorrect Answers:
Answer 1: Acyclovir is used to treat cold sores (herpes labialis), which are caused by reactivation of a herpes simplex virus (HSV) infection. Acyclovir is converted into an active metabolite that competitively inhibits viral DNA polymerase. Recurrent herpes labialis lesions appear as clusters of vesicles on the lips rather than inside the oral cavity and may be preceded by pain, burning, tingling, or itching. HSV reactivation would not account for the GI or hematologic signs/symptoms seen in this patient.

Answer 2: Benzathine penicillin G is used to treat syphilis. Although oral ulcerations can be present in primary syphilis, the lesion (chancre) appears as a singular 1-2 centimeter ulcer with raised borders and is usually painless. Chancres are infectious lesions filled with bacteria (Treponema pallidum) and represent the site of entry. Syphilis would not account for this patient’s GI symptoms and symptomatic anemia.

Answer 3: Budesonide is a corticosteroid typically used for the treatment of Crohn disease. Although Crohn disease can cause painful oral ulcerations and diarrhea, crampy abdominal pain would also be expected. Crohn disease can affect various sites along the entire GI tract (e.g., aphthous oral and duodenal ulcers) and presents with transmural bowel inflammation resulting in fistulas and strictures. Extra-intestinal manifestations include arthropathy, erythema nodosum, and pyoderma gangrenosum.

Answer 5: Prednisone is used in the management of systemic lupus erythematosus (SLE) flares. SLE would be expected to present with other characteristic findings such as fever, malar or discoid rash, and/or deficiencies in multiple blood cell lines (e.g., pancytopenia). Although SLE can cause mucositis, methotrexate side effect is more likely in this patient who developed oral ulcers after the recent initiation of methotrexate treatment.

Bullet Summary:
Methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase and can cause GI, hematologic, and mucosal (e.g., oral ulcers) side effects via functional folate depletion, which is treated with folate supplementation.